This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project 1: Thrombospondin1 mediates macrophage infiltration into adipose tissue and promotes atherosclerosis in obese mice PI Shuxia Wang Description: Obesity is becoming a global public health problem and is associated with an increased risk of atherosclerosis. Accumulating evidence suggests that obesity-induced chronic low-grade inflammation is an important mechanism for the adverse effects of adiposity on atherosclerosis. Thrombospondin1 (TSP1), a multifunctional extracellular matrix protein with multi-domains, exhibits several effects on the vasculature that would be anticipated to contribute to the development and progression of atherosclerosis. TSP1 has been shown to be up-regulated in adipose tissue of mice with diet or genetically induced obesity. Moreover, recent studies demonstrate that TSP1 expression is increased in adipocytes from obese humans and correlates positively to obesity and adipose tissue inflammation. Preliminary data demonstrate that adipose tissue from high fat (HF)-fed TSP1 deficient mice exhibits reduced numbers of infiltrating macrophages compared to HF-fed wild type controls. Importantly, reductions in macrophage infiltration into adipose tissue of TSP1-/- HF-fed mice were observed even though mice exhibited similar levels of obesity as wild type controls. Based on these studies, we hypothesize that specific domains of TSP1 mediate increased macrophage infiltration into adipose tissue with diet-induced obesity and promote atherosclerosis in apoE-/- mice. To address this hypothesis, we will determine the specific domains of TSP1 responsible for increased macrophage adhesion and/or migration in Aim 1 and determine if TSP1 deficiency decreases atherosclerosis in apoE-/- mice with diet-induced obesity in Aim 2. These studies will provide novel information on the role of TSP1 in obesity associated atherosclerosis and may lead to development of therapeutic targets for treatment of this disease.